One noted investigator posed the following questions in lectures: (1)
What is the most curable solid tumor? (Answer: testicular cancer);
(2) What is the second most curable solid tumor? (Answer: recurrent
testicular cancer). In light of the fact that germ-cell tumors are
the poster child for medical oncology, there is certainly truth to
Over the last quarter of a century, our understanding of the biology
and treatment of this disease has grown impressively. As Dr. Srinivas
notes, 95% of all patients with testicular cancer should be cured
with appropriate therapy. For those patients with disseminated
disease, however, the prognosis varies with the extent and level of
serum markers. The International Germ Cell Consensus Classification
underscores the relationship of primary site (mediastinum vs other)
serum markers (betahuman chorionic gonadotropin [HCG],
alpha-fetoprotein [AFP], lactic dehydrogenase [LDH]), extent of
disease, and histology (seminoma vs nonseminomatous germ-cell tumor)
In contrast to acute leukemia, where a similar percentage of patients
achieve a complete remission, relapse from complete remission in
germ-cell tumors following induction chemotherapy is 10% or less.
Fortunately, the number of patients who have an incomplete response
or relapse from primary therapy is low, with only a few hundred such
patients seen in the United States each year. Nonetheless, patients
with a poor prognosis are precisely the ones in whom novel treatment
approaches are required.
This article highlights several questions, including whether
high-dose chemotherapy is an effective strategy in germ-cell tumors.
The concept of dose intensity has permeated the oncology literature
for many years. As mentioned by Dr. Srinivas, a dose threshold for
cisplatin (Platinol) was demonstrated by the Southwest Oncology Group
(SWOG) several years ago. The latter trial, conducted by Indiana
University and SWOG, demonstrated that doubling the dose of cisplatin
from 20 mg/m² to 40 mg/m², both given on days 1
through 5, not only failed to improve complete remission or overall
survival rates, but also substantially increased the incidence of
grade 4 neuropathy. Other trials mentioned by Dr. Srinivasusing
modest increases in dosages of cisplatin or etoposidehave
demonstrated either little or minimal support for higher-dose therapy
in this disease.
In the salvage setting, high-dose chemotherapy with stem-cell rescue
has proven effective for a patient population not felt to be curable
with standard therapy. With such an approach, 15% to 21% of
heavily pretreated patients may achieve a durable, complete
remission. These trials have encouraged the earlier use of this
therapy in patients with first relapse or even as part of primary
therapy, thereby leading to a seemingly better outcome. In addition,
earlier treatment and patients with a better performance status have
resulted in decreased morbidity and mortality of therapy in this population.
In patients with recurrent testicular cancer (excluding an
extragonadal primary) whose disease is not cisplatin
refractory (ie, progressing within 3 to 4 weeks of prior cisplatin),
a 50% cure rate has been observed with tandem transplants. This
contrasts with an approximate 30% cure rate for those treated with
conventional doses of VIP (vinblastine, ifosfamide [Ifex], cisplatin)
in a similar patient population as part of second-line therapy.
These data reaffirm the observation that selection bias may alter
results. Patients with primary mediastinal tumors, patients who
progress within 3 weeks of prior chemotherapy, and patients with
nongerm-cell malignancies associated with teratoma do not fare
well with standard salvage or high-dose chemotherapy with stem-cell rescue.
Another group with unfavorable results are those patients who develop
recurrences beyond 2 years from primary therapy. Although brief
objective responses are seen with chemotherapy, only those patients
who have disease that is surgically extirpated are associated with
long-term survival. Similarly, although some brief remissions are
seen in patients who relapse following high-dose chemotherapy and
stem-cell rescue, this response rate is less than 20%, which includes
about 5% who were long-term survivors requiring surgical extirpation
of disease as part of their treatment armamentarium.
Another question is whether a role exists for high-dose chemotherapy
as part of primary chemotherapy in patients with poor-risk disease.
This is the objective of an ongoing prospective, randomized trial
that is evaluating standard BEP (bleomycin [Blenoxane], etoposide,
Platinol) to two cycles of BEP followed by high-dose carboplatin
(Paraplatin), etoposide, and cyclophosphamide (Cytoxan, Neosar) with
stem-cell rescue. This is an extremely important trial that is still
Outside the confines of a clinical trial, we are often asked whether
bone marrow transplantation should be used as part of initial
induction therapy for patients whose serum markers seem to be
declining at a rate less than predicted. Although this is an
interesting concept, many of these patients treated with standard
therapy will continue to respond to treatment.
In addition, several factors may also be associated with a slower
decline of serum markers, including occult central nervous system
metastases, an intact primary in the testis, or false marker
elevations secondary to marijuana use (elevated HCG) or hepatitis
(elevated AFP). Since virtually all patients respond to initial
induction chemotherapy, this will be a difficult concept to test prospectively.
In summary, high-dose chemotherapy with peripheral stem-cell rescue
has an essential role as part of salvage chemotherapy in patients
with recurrent, but cisplatin-sensitive, disease. When performed at
established centers, the mortality rate should be considerably less
than 5%. The high degree of activity in this setting has prompted an
evaluation of this strategys role in primary therapy for
patients with poor-risk disease. We believe that until this trial is
completed, front-line use of high-dose therapy remains investigational.
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